Use of organophosphorus compounds for the therapeutic and prophylactic treatment of infections

ABSTRACT

Use of organophosphorus compounds of general Formula (I)  
                 
 
     for the therapeutic and prophylactic treatment of infections in humans and animals caused by viruses, fungi and parasites.

[0001] The invention relates to the use of organophosphorus compoundsand their salts, esters and amides for the therapeutic and prophylactictreatment of infections which are caused by viruses, fungi and parasitesin humans and animals. According to the invention the organophosphoruscompounds comprise phosphonic acid derivatives, phosphinoyl derivatesand phosphinic acid derivatives.

[0002] The suitability of aminohydrocarbyl phosphonic acid derivates andsome of their esters and salts for use in pharmaceutical compositions isalready known. Up until now however only their antimicrobial efficacyagainst bacteria in humans and animals and against fungi in plants hasbeen described (DE 27 33 658 A1, U.S. Pat. No. 4,143,135, U.S. Pat. No.4,182,758 and U.S. Pat. No. 4,206,156, U.S. Pat. No. 4,994,447, U.S.Pat. No. 4,888,330, U.S. Pat. No. 4,210,635, U.S. Pat. No. 3,955,958,U.S. Pat. No. 4,196,193, U.S. Pat. No. 4,268,503, U.S. Pat. No.4,330,529, U.S. Pat. No. 5,189,030, U.S. Pat. No. 3,764,677, U.S. Pat.No. 3,764,676). Furthermore substances from this group have beendescribed as herbicides (U.S. Pat. No. 4,693,742, U.S. Pat. No.5,002,602, U.S. Pat. No. 4,131,448, U.S. Pat. No. 3,977,860, U.S. Pat.No. 4,062,669), as algaecides (U.S. Pat. No. 3 887 353), as means forregulating plant growth (U.S. Pat. No. 4,127,401, U.S. Pat. No.4,120,688, U.S. Pat. No. 3,961,934, U.S. Pat. No. 4,431,438, U.S. Pat.No. 3,853,530, U.S. Pat. No. 4,205,977, U.S. Pat. No. 4,025,332, U.S.Pat. No. 3,894,861) and as reagents in dye production (U.S. Pat. No.4,051,175). In DE 27 33 658 A1 the use of aminohydrocarbyl phosphonicacid derivatives for the treatment of bacterial diseases has beendescribed. Whilst the document speaks of a microbial efficacy againstpathogenic microorganisms in the introduction to the description, fromthe overall context however it is clear that the invention relatesexclusively to bacteria. Thus on page 16, second paragraph“antimicrobial efficacy” is defined as “antibacterial efficacy”.

[0003] There is a serious need for the provision of preparations toenhance the treatment of humans and animals and the protection ofplants, which preparations not only possess a strong efficacy but incontrast to other pharmaceutical compositions and plant protectiveagents, contain reduced side effects and therefore represent a lowerrisk to health for humans.

[0004] The object of the present invention is therefore to provide asubstance which fulfils the conditions given above in the case ofinfections caused by viruses, fungi and parasites in humans and animals.

[0005] This object is achieved in a completely surprising manner by thegroup of substances defined in claim 1. This group of substancesdemonstrates an anti-infectious effect against viruses, fungi andunicellular and multicellular parasites. In the context of thisinvention the strictly scientific definition of parasites is to be used.This means that unicellular parasites are understood to mean protozoaexclusively.

[0006] The organophosphorus compounds used according.to the inventioncorrespond to the general Formula (I):

[0007] in which R₁ and R₂ are the same or different and are selectedfrom the group which consists of hydrogen, substituted and unsubstitutedalkyl, substituted and unsubstituted hydroxyalkyl, substituted andunsubstituted alkenyl, substituted and unsubstituted alkinyl,substituted and unsubstituted aryl, substituted and unsubstituted acyl,substituted and unsubstituted cycloalkyl, substituted and unsubstitutedaralkyl, substituted and unsubstituted heterocyclic radical, halogen,OX₁ and OX₂, wherein X₁ and X₂ can be the same or different and areselected from the group which consists of hydrogen, substituted andunsubstituted alkyl, substituted and unsubstituted hydroxyalkyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkinyl, substituted and unsubstituted aryl, substituted andunsubstituted acyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted aralkyl, substituted and unsubstitutedheterocyclic radicals,

[0008] A is selected from the group which consists of an alkyleneradical, an alkenylene radical and a hydroxyalkylene radical,

[0009] R₃ and R₄ are selected independently from the group whichconsists of hydrogen, substituted and unsubstituted C₁₋₂₆-alkyl,substituted and unsubstituted hydroxy-C₁₋₂₆-alkyl, substituted andunsubstituted aryl, substituted and unsubstituted acyl, substituted andunsubstituted aralkyl, substituted and unsubstituted C₁₋₂₆-alkenyl,substituted and unsubstituted C₁₋₂₆-alkinyl, substituted andunsubstituted cycloalkyl, substituted and unsubstituted heterocyclicradical, halogen, OX₃ and OX₄,

[0010] wherein X₃ and X₄ are selected independently from the group whichconsists of hydrogen, substituted and unsubstituted C₁₋₂₆- alkyl,substituted and unsubstituted hydroxyl-C₁₋₂₆ -alkyl, substituted andunsubstituted aryl, substituted and unsubstituted aralkyl, substitutedand unsubstituted C₁₋₂₆- alkenyl, substituted and unsubstitutedCl₁₋₂₆-alkinyl, substituted and unsubstituted cycloalkyl, substitutedand unsubstituted heterocyclic radical, a silyl, a cation of an organicand inorganic base, in particular a metal of the first, second or thirdmain group of the periodic system, ammonium, substituted ammonium andammonium compounds which derive from ethylene diamine or amino acids,

[0011] and their pharmaceutically acceptable salts, esters and amidesand salts of esters.

[0012] Phosphonic acid derivatives are particularly preferred.

[0013] In particular compounds which contain the following Formula (II)are suitable:

[0014] wherein,

[0015] X₁ is selected from the group which consists of hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,substituted or unsubstituted cycloalkyl, substituted and unsubstitutedheterocyclic radical;

[0016] R₂, R₃, R₄ and A contain the same meaning as in Formula (I).

[0017] A is particularly preferably a chain of three carbon atoms whichbind the nitrogen atom to the phosphorus atom.

[0018] Compounds of Formula (II) are particularly preferred in whichR₂=acyl, in particular an acetyl, R₃=hydrogen, methyl or ethyl,R₄=hydrogen, methyl, ethyl or OX₄ with X₄=hydrogen, sodium, potassium,methyl, ethyl, X₁=H and A=alkylene, alkenylene or hydroxyalkylene.Particularly good results are achieved with R₂=formyl or acetyl andA=propylene, propenylene or hydroxypropylene.

[0019] Furthermore compounds are particularly preferred in which R₃ isan alkyl, hydroxyalkyl, alkinyl, or alkenyl group with 16 or 18 carbonatoms or OX₃, wherein X₃ is an alkyl, alkinyl, hydroxyalkyl or alkenylgroup with 16 or 18 carbon atoms, R₄ is an alkyl, alkinyl, hydroxyalkylor alkenyl group with 16 or 18 carbon atoms or OX₄, wherein X₄ is analkyl, alkinyl, hydroxyalkyl or alkenyl group with 16 or 18 carbonatoms.

[0020] Special features of the above definitions and suitable examplesthereof are given below:

[0021] “Acyl” is a substituent which originates from an acid such asfrom an organic carboxylic acid, carbonic acid, carbamic acid or thethioacid or imidic acid corresponding to the individually present acids,or from an organic sulphonic acid, wherein these acids comprise in eachcase aliphatic, aromatic and/or heterocyclic groups in the molecule andcarbamoyl or carbamimidoyl.

[0022] Suitable examples of these acyl groups will be given below.

[0023] Acyl radicals originating from an aliphatic acid are designatedas aliphatic acyl groups and include:

[0024] Alkanoyl (for example formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl etc.);

[0025] Alkenoyl (for example acryloyl, methacryloyl, crotonoyl etc.);

[0026] Alkylthioalkanoyl (for example methylthioacetyl, ethylthioacetyletc.);

[0027] Alkane sulphfonyl (for example mesyl, ethane sulphonyl, propanesulphonyl etc.);

[0028] Alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyletc.);

[0029] Alkylcarbamoyl (for example methylcarbamoyl etc.);

[0030] (N-alkyl)-thiocarbamoyl (for example (N-methyl)-thiocarbamoyletc.);

[0031] Alkylcarbamimidoyl (for example methylcarbamimidoyl etc.);

[0032] Oxalo;

[0033] Alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc.).

[0034] In the above examples of aliphatic acyl groups the aliphatichydrocarbon part, in particular the alkyl group and the alkane radicalcan optionally contain one or more suitable substituents such as amino,halogen (for example fluorine, chlorine, bromine etc.), hydroxy,hydroxyimino, carboxy, alkoxy (for example methoxy, ethoxy, propoxyetc.), alkoxycarbonyl, acylamino (for example benzyloxycarbonylaminoetc.), acyloxy (for example acetoxy, benzoyloxy etc.) and the like.Preferred aliphatic acyl radicals with such substitutes are for examplealkanoyls substituted with amino, carboxy, amino and carboxy, halogen,acylamino or the like.

[0035] Acyl resides originate from an acid with substituted orunsubstituted aryl groups, wherein the aryl group can comprise phenyl,toluyl, xylyl, naphthyl, and the like are designated as aromatic acylradicals. Suitable examples are given below:

[0036] Aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyletc.);

[0037] Aralkanoyl (for example phenylacetyl etc.);

[0038] Aralkenoyl (for example cinnamoyl etc.);

[0039] Aryloxyalkanoyl (for example phenoxyacetyl etc.);

[0040] Arylthioalkanoyl (for example phenylthioacetyl etc.);

[0041] Arylaminoalkanoyl (for example N-phenylglycyl, etc.);

[0042] Arene sulphonyl (for example benzene sulphonyl, tosyl toluenesulphonyl, naphthalene sulphonyl etc.);

[0043] Aryloxycarbonyl (for example phenoxycarbonyl,naphthyl-oxycarbonyl etc.);

[0044] Aralkoxycarbonyl (for example benzyloxycarbonyl etc.);

[0045] Arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyletc.);

[0046] Arylglyoxyloyl (for example phenylglyoxyloyl etc.).

[0047] In the above-mentioned examples of aromatic acyl radicals thearomatic hydrocarbon part. (in particular the aryl radical) and/or thealiphatic hydrocarbon part (in particular the alkane radical) canoptionally contain one or more suitable substituents such as those whichwere already mentioned as suitable substituents for the alkyl group andthe alkane radical. In particular and as an example of preferredaromatic acyl radicals with particular substituents, aroyl substitutedby halogen and hydroxy or by halogen and acyloxy and aralkanoylsubstituted by hydroxy, hydroxyimino, dihalogenalkanoyloxyimino arementioned as well as

[0048] Arylthiocarbamoyl (for example phenylthiocarbamoyl etc.);

[0049] Arylcarbamimidoyl (for example phenylcarbamimidoyl etc.).

[0050] A heterocyclic acyl radical is understood to be an acyl radicalwhich originates from an acid with hererocyclic group. These include:

[0051] Heterocyclic carbonyl, in which the heterocyclic radical is anaromatic or aliphatic 5 to 6 membered heterocycle with at least oneheteroatom from the group nitrogen, oxygen and sulphur (for examplethiophenyl, furoyl, pyrrolcarbonyl, nicotinoyl etc.);

[0052] Heterocyclic alkanoyl in which the heterocyclic radical is 5 to 6membered and has at least one heteroatom from the group nitrogen, oxygenand sulphur (for example thiophenylacetyl, furylacetyl,imidazolylpropionyl, tetrazolylacetyl,2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl etc.) and the like.

[0053] In the above examples of heterocyclic acyl radicals theheterocycles and/or the aliphatic hydrocarbon part can optionallycontain one or more suitable substituents, such as the same as thosewhich were mentioned as suitable for alkyl and alkane groups.

[0054] “Alkyl” is a straight- or branched-chain alkyl radical with up to9 carbon atoms, unless defined otherwise, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.

[0055] “Hydroxylalkyl” is a straight- or branched-chain alkyl radicalwith up to 9 carbon atoms, unless defined otherwise, which contains atleast one hydroxyl group, preferably one or two hydroxyl groups.

[0056] “Alkenyl” includes straight- or branched-chain alkenyl groupswith up to 9 carbon atoms, unless defined otherwise, such as, forexample, vinyl, propenyl, (for example 1-propenyl, 2-propenyl),1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl,hexenyl.

[0057] “Alkinyl” includes straight- or branched-chain alkinyl groupswith up to 9 carbon atoms, unless defined otherwise.

[0058] Cycloalkyl preferably represents an optionally substituted C3 toC7 cycloalkyl. Alkyl, alkenyl, alkinyl, alkoxy (for example methoxy,ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.),nitrc and the like are inter alia suitable as possible substituents.

[0059] Aryl is an aromatic hydrocarbon radical such as phenyl naphthyletc., which can optionally contain one or more suitable substituentssuch as alkyl, alkenyl, alkinyl, alkoxy (for example methoxy, ethoxyetc.), halogen (for example fluorine, chlorine, bromine etc.), nitro andthe like.

[0060] “Aralkyl” includes mono-, di-, triphenylalkyls such as benzyl,phenethyl, benzhydryl, trityl and the like, wherein the aromatic partcan optionally contain one or more suitable substituents such as alkoxy(for example methoxy, ethoxy etc.), halogen (for example fluorine,chlorine, bromine etc.), nitro and the like.

[0061] “Alkylene” includes straight- or branched-chain alkylene groupswhich contain up to 9 carbon atoms and can be reproduced by the Formula

—(C_(n)H_(2n))—

[0062] in which n is an integer from 1 to 9, such as methylene,ethylene, trimethylene, methylethylene, tetramethylene,1-methyltrimethylene, 2-ethylethylene, pentamethylene,2-methyltetramethylene, isopropylethylene, hexamethylene, and the like.Preferred alkylene radicals contain up to 4 carbon atoms and radicalswith 3 carbon atoms such as, for example, trimethylene are particularlypreferred. The hydrogen atoms can be replaced by other substituents suchas, for example, halogen radicals.

[0063] “Alkenylene” includes straight- or branched-chain alkenylenegroups with up to 9 carbon atoms which can be reproduced by the Formula

—(CH₂H_(2n−2))—

[0064] in which n is an integer from 2 to 9, such as, for example,vinylene, propenylene (for example 1-propenylene, 2-propenylene),1-methylpropenylene, 2-methylpropenylene, butenylene,2-ethylpropenylene, pentenylene, hexenylene and the like. The alkenyleneradical can particularly preferably contain up to 5 carbon atoms and inparticular 3 carbon atoms such as, for example, 1-propenylene. Thehydrogen atoms can be replaced by other substituents such as, forexample, halogen radicals.

[0065] “Hydroxyalkylene” can include straight- or branched-chainalkylene radicals which contain up to 9 carbon atoms, wherein at leastone selected carbon atom is substituted by a hydroxy group. Theseradicals can be reproduced by the Formula

—(C_(n)H_(2n−z))(OH)_(z)—

[0066] in which n is an integer from 1 to 9 and z is an integer, towhich 1≦z≦n applies. Suitable examples of such hydroxyalkylene groupsinclude hydroxymethylene, hydroxyethylene (for example 1-hydroxyethyleneand 2-hydroxyethylene), hydroxytrimethylene (for example1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene),hydroxy-tetramethylene (for example 2-hydroxytetramethylene),2-hydroxy-2-methyltrimethylene, hydroxypentamethylene (for example2-hydroxypentamethylene), hydroxyhexamethylene (for example2-hydroxyhexamethylene) and the like. A lower hydroxyalkylene with up to4 carbon atoms is particularly preferred and in particular one with 3carbon atoms such as, for example, 2-hydroxytrimethylene. The hydrogenatoms can be replaced by other substituents such as, for example,halogen radicals.

[0067] The radicals X₃ and X₄ can preferably be selected such thatesters form on the phosphinic group or phosphonic group. Suitableexamples of such esters in accordance with the Formulae (I) and (II)include alkyl esters (for example methyl ester, ethyl ester, propylester, isopropyl ester, butyl ester, isobutyl ester, hexyl ester,hexadecanyl ester, octadecanyl ester etc.);

[0068] Aralkyl esters (benzyl ester, phenethyl ester, benzohydryl ester,trityl ester etc.);

[0069] Aryl esters (for example phenyl ester, tolyl ester, naphthylester etc.);

[0070] Aroylalkyl esters (for example phenacyl ester etc.); and silylesters (for example from trialkylhalogensilyl, dialkyldihalogensilyl,alkyltrihalogensilyl, dialkylaryl-halogensilyl, trialkoxyhalogensilyl,dialkylaralkylhalogensilyl, dialkoxydihalogensilyl,trialkoxyhalogensilyl etc.) and the like.

[0071] With the above esters the alkane and/or arene part can contain atleast one suitable substituent as desired such as halogen, alkoxy,hydroxy, nitro or the like.

[0072] X₃ and X₄ are preferably a metal from the first, second or thirdmain group of the periodic system, ammonium, substituted ammonium orammonium compounds which derive from ethylenediamine or amino acids. Inother words the salt compounds of organophosphorus compounds are formedwith organic or inorganic bases (for example sodium salt, potassiumsalt, calcium salt, aluminium salt, ammonium salt, magnesium salt,triethylamine salt, ethanolamine salt, dicyclohexylamine salt,ethylenediamine salt, N,N′-dibenzylethylenediamine salt etc.) and saltswith amino acids (for example arginine salt, aspartic acid salt,glutamic acid salt etc.) and the like.

[0073] The compounds used according to the invention in accordance withthe Formulae (I) or (II) can be present in their protonised form asammonium salt of organic or inorganic acids such as hydrochloric acid,hydrobromic acid, sulphuric acid, nitric acid, methane sulphonic acid,p-toluene sulphonic acid, acetic acid, lactic acid, maleic acid, fumaricacid, oxalic acid, tartaric acid, benzoic acid etc.

[0074] The compounds used according to the invention of Formulas (I) or(II) permit for example the emergence of spatial isomers for groupscontaining double bonds or chiral groups R₁, R₂, R₃, R₄, x₁, X₂, X₃, X₄or A. The use of compounds according to the invention consists of allspatial isomers both as pure substances and in the form of theirmixtures.

[0075] The organophosphorus compounds are suitable in particular for thetherapeutic and prophylactic treatment of infections in humans andanimals which are caused by viruses, unicellular and multicellularparasites and fungi.

[0076] The compounds are effective against unicellular parasites(protozoa), in particular against pathogens of malaria and sleepingsickness as well as Chagas' disease, toxoplasmosis, amoebic dysentery,leishmaniasis, trichomoniasis, pneumocystosis, balantidiasis,cryptosporidiasis, sarcocystosis, acanthamebiasis, naegleriasis,coccidiosis, giardiasis and lambliosis.

[0077] They are therefore particularly suitable as malaria prophylacticsand as prophylactics for sleeping sickness as well as Chagas' disease,toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis,pneumocystosis, balantidiasis, cryptosporidiasis, sarcocystosis,acanthamebiasis, naegleriasis, coccidiosis, giardiasis and lambliosis.

[0078] Combinations with an antibiotic can also be used to treat theabove-mentioned diseases. Isoniazid, rifampicin, ethambutol,pyrazineamide, streptomycin, protionamide and dapsone are particularlysuitable for combination with other anti-infectives for the treatment oftuberculosis.

[0079] The agents according to the invention can furthermore be used inparticular in infections with the following viruses:

[0080] Parvoviridae: parvo viruses, dependo viruses, denso viruses,Adenoviridae: adeno viruses, mastadeno viruses, aviadeno viruses,

[0081] Papovaviridae: papova viruses, in particular papilloma viruses(so called wart viruses), polyoma viruses,. in particular JC virus, BKvirus and miopapova viruses,

[0082] Herpesviridae: all herpes viruses, in particular herpes simplexviruses, varicella-zoster viruses, human cytomegalo virus, Epstein-Barrviruses, all human herpes viruses, human herpes virus 6, human herpesvirus 7, human herpes virus 8, Poxviridae: pox viruses, orthopox,parapox, molluscum contagiosum virus, avipox viruses, capripox viruses,leporipox viruses, all primary hepatotropic viruses, hepatitis viruses:hepatitis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitisD viruses, hepatitis E viruses, hepatitis F viruses, hepatitis Gviruses,

[0083] Hepadna viruses: all hepatitis viruses, hepatitis B virus,hepatitis D viruses,

[0084] Picornaviridae: picorna viruses, all entero viruses, all polioviruses, all coxsackie viruses, all echo viruses, all rhino viruses,hepatitis A virus, aphtho viruses,

[0085] Calciviridae: hepatitis E viruses,

[0086] Reoviridae: reo viruses, orbi viruses, rota viruses, Togaviridae:toga viruses, alpha viruses, rubi viruses, pestiviruses, rubella virus,

[0087] Flaviviridae: flavi viruses, ESME virus, hepatitis C virus,

[0088] Orthomyxoviridae: all influenza viruses,

[0089] Paramyxoviridae: paramyxo viruses, morbilli virus, pneumo virus,measles virus, mumps virus

[0090] Rhabdoviridae: rhabdo viruses, rabies virus, lyssa virus, visculastomatitis virus,

[0091] Coronaviridae: corona viruses,

[0092] Bunyaviridae: bunya viruses, nairo virus, phlebo virus, uukuvirus, hanta virus, hantaan virus,

[0093] Arenaviridae: arena viruses, lymphocytic choriomeningitis virus,

[0094] Retroviridae: retro viruses, all HTL viruses, human T-cellleukaemia virus, oncorna viruses, spuma viruses, lenti viruses, all HIviruses,

[0095] Filoviridae: Marburg and Ebola virus,

[0096] Slow virus infections, prions,

[0097] Oncoviruses and leukaemia viruses.

[0098] The organophosphorus compounds used according to the inventionare therefore suitable for fighting the following viral infections:

[0099] Eradication of papilloma viruses to prevent tumours, inparticular tumours in the sexual organs caused by papilloma viruses inhumans, eradication of JC viruses and BK viruses, eradication of herpesviruses, eradication of human herpes viruses 8 for the treatment ofKaposi's sarcoma, eradication of cytomegalo viruses before transplants,eradication of Epstein-Barr viruses before transplants and to preventtumours associated with Epstein-Barr viruses, eradication of hepatitisviruses for the treatment of chronic liver diseases and for theprevention of tumours of the liver and cirrhosis of the liver,eradication of coxsackie viruses in patients with cardiomyopathy,eradication of coxsackie viruses in diabetes mellitus patients,eradication of immune system debilitating viruses in humans and animals,treatment of secondary infections in AIDS patients, treatment ofinflammations of viral origin of the respiratory tract (larynxpapillomas, hyperplasias, rhinitis, pharyngitis, bronchitis,pneumonias), of the sensory organs (keratoconjunctivitis), of thenervous system (poliomyelitis, meningoencephalitis, encephalitis,subacute sclerosing panencephalitis SSPE, progessive multifocalleukoencephalopathy, lymphocytic choriomeningitis), of thegastro-intestinal tract (stomatitis, gingivostomatitis, oesophagitis,gastritis, gastroenteritis, diarrhoea-causing diseases), of the liverand gall bladder system (hepatitis, cholangitis, hepatocellularcarcinoma), of the lymphatic tissue (mononucleosis, lymphadenitis), ofthe haematopoetic system, of the sexual organs (mumpsorchitis), of theskin (warts, dermatitis, herpes labialis, heat rash, herpes zoster,shingles), of the mucous membranes (papillomas, conjunctiva papillomas,hyperplasias, dysplasias), of the heart/blood vessel system (arteritis,myocarditis, endocarditis, pericarditis), of the kidney/urinary tractsystem, of the sexual organs (anogenital lesions, warts, genital warts,acute condylomas, displasias, papillomas, cervix dysplasias, condylomataacuminata, epidermodysplasia verruci formis), of the organs_of motion(myositis, myalgias), treatment of foot and mouth diseases incloven-hoofed animals, of Colorado tick fever, of Dengue syndrome, ofhaemorrhagic fever, of early summer meningoencephalitis (ESME) and ofyellow fever.

[0100] The described compounds, i.e. the organophosphorus compoundsaccording to Formulae (I) and (II) and esters and amides thereof on thephosphinic group or phosphonic group and salts thereof have a stronglycytotoxic efficacy against unicellular and multicellular parasites, inparticular against pathogens of malaria and sleeping sickness.Accordingly the compounds used according to the invention can be usedfor the treatment of infectious diseases which are caused by viruses,parasites and fungi in humans and animals. The compounds are alsosuitable for use in the prevention of diseases which are caused byviruses, parasites and fungi, in particular as malaria prophylactics andas sleeping sickness prophylactics.

[0101] The organophosphorus compounds used according to the invention,which generally include pharmaceutically acceptable salts, amides,esters, a salt of such an ester or else compounds which upon applicationprovide the compounds used according to the invention as metabolicproducts or decomposition products, also called “prodrugs”, can allprepared for administration like known anti-infectious agents in anysuitable manner (mixed with a non-toxic pharmaceutically acceptablecarrier).

[0102] Pharmaceutically acceptable salts of the compounds include saltswhich form the compounds used according to the invention of Formulae (I)and (II) in their protonised form as an ammonium salt of inorganic ororganic acids, such as hydrochloric acid, sulphuric acid, citric acid,maleic acid, fumaric acid, tartaric acid, p-toluene sulphonic acid.

[0103] Salts which are formed by suitable selection of X₃ and X₄ such assodium salt, potassium salt, calcium salt, ammonium salt, ethanolaminesalt, triethylamine salt, dicylcohexylamine salt and salts of an aminoacid such as arginine salt, aspartic acid salt, glutamine acid salt areparticularly suitable pharmaceutically.

[0104] The activity of substances is determined in a test system. Thissystem is based on the measuring of the inhibition of growth ofparasites, viruses, fungi or plants in vitro. To this end, testprocedures are used, some of which are known to the person skilled inthe art.

[0105] To determine the anti-malaria activity, for example, theinhibition of the growth of malaria parasites in blood cultures isdetermined.

[0106] The determining of antiviral activity is based on inhibition ofthe formation of viral elements in cell cultures.

[0107] The determining of fungicidal activity is based on the inhibitionof the growth of fungi on culture media and in liquid cultures.

[0108] Some of the microorganisms which should be investigated can onlybe investigated in animal models. In this case we will use thecorresponding models.

[0109] Substances which demonstrate an efficacy in the in vitromeasuring systems will be further investigated in in vivo models.

[0110] The anti-parasitic, antiviral or fungicide activity will befurther evaluated in the appropriate animal models.

[0111] The pharmaceutically effective preparations can be prepared inthe form of pharmaceutical preparations in dispensing units. This meansthat the preparation can be present in the form of individual parts, forexample tablets, dragees, capsules, pills, suppositories and ampoules,the active ingredient content of which corresponds to a fraction or amultiple of a single dose. The dispensing units can, for example,contain 1, 2, 3 or 4 single doses or ½, ⅓ or ¼ of a single dose. Asingle dose preferably contains the quantity of active ingredient whichis administered during one application and which usually corresponds toa whole, a half or a third or a quarter of a daily dose.

[0112] Non-toxic, inert pharmaceutically suitable excipients areunderstood to mean solid, semi-solid or liquid diluents, fillers andformulation auxiliary agents of all kinds.

[0113] Tablets, dragees, capsules, pills, granules, suppositories,solutions, suspensions and emulsions, pastes, ointments, gels, creams,lotions, powders and sprays are mentioned as suitable pharmaceuticalpreparations. Tablets, dragees, capsules, pills and granules can containin addition to the conventional excipients, the active ingredient oractive ingredients such as (a) fillers and diluents, for examplestarches, lactose, cane sugar, glucose, mannitol and silicic acid, (b)binders, for example carboxymethylcellulose, alginates, gelatines,polyvinylpyrrolidone, (c) moisture-retaining agents, for exampleglycerol, (d) dispersing agents, for example agar-agar, calciumcarbonate and sodium carbonate, (e) solution retarders, for exampleparaffin and (f) resorption accelerators, for example quaternaryammonium compounds, (g) wetting agents, for example cetyl alcohol,glycerol monostearate, (h) adsorption agents, for example kaolin andbetonite and (i) lubricants, for example talcum, calcium and magnesiumstearate and solid polyethylene glycols or mixtures of the substanceslisted under (a) to (i).

[0114] The tablets, dragees, capsules, pills and granular materials canbe provided with the conventional coatings and casings optionallycontaining opaquing agents and can also be put together so that theyrelease the active ingredient or active ingredients only or preferablyin a specific part of the intestinal tract optionally with sustainrelease, wherein polymer substances and waxes for example can be used asembedding compounds.

[0115] The active ingredient or active ingredients can optionally alsobe present in microencapsulated form with one or more of theabove-mentioned excipients.

[0116] In addition to the active ingredient or active ingredientssuppositories can also contain the conventional water soluble or waterinsoluble excipients, for example polyethylene glycols, fats, forexample cocoa fat and higher esters (for example C14-alcohol withC16-fatty acid) or mixtures of these substances.

[0117] In addition to the active ingredient or active ingredients,ointments, pastes, creams and gels can contain the conventionalexcipients, for example animal and vegetable fats, wakes, paraffins,starches, .tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, talc and zinc oxide or mixtures ofthese substances.

[0118] In addition to the active ingredient or active ingredients,powders and sprays can contain the conventional excipients, for examplelactose, talc, silicic,acid, aluminium hydroxide, calcium silicate, andpolyamide powder or mixtures of these substances. Sprays canadditionally contain the conventional blowing agents, for examplechlorofluorohydrocarbons.

[0119] In addition to the active ingredient or active ingredients,solutions and emulsions can contain the conventional excipients. such assolvents, solubilisers and emulsifiers, for example water, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils, in particular cotton seed oil, peanut oil,corn oil, olive oil, castor oil and sesame oil, glycerol, glycerolformal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan or mixtures of these substances.

[0120] The solutions and emulsions can also be present in sterile andblood isotonic form for parenteral application.

[0121] In addition to the active ingredient or active ingredients,suspensions can contain conventional excipients such as liquid diluents,for example water, ethyl alcohol, propylene glycol, suspending agents,for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitoland sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar and tragacanth or mixtures of thesesubstances.

[0122] The above-mentioned formulations can also contain dyes,preservatives and odour and flavour improving additives, for examplepeppermint oil and eucalyptus oil and sweeteners, for examplesaccharine.

[0123] The agents of Formulae (I) and (II) should be present in theabove-listed pharmaceutical preparations preferably in a concentrationof approximately 0.1 to 99.5% by weight, preferably of approximately 0.5to 95% by weight of the total mixture.

[0124] In addition to the compounds of Formulae (I) and (II) thepharmaceutical preparations can also contain further pharmaceuticalagents.

[0125] The compounds can be used with hitherto described substances withantibacterial, antiviral, antifungal and antiparasitic properties.Compounds which have already found application in treatment or are stillbeing used belong to this group. Substances. which are listed in the RedList or in Simon/Stille, Antibiotika-Therapie in Klinik und Praxis, 9thEdition 1998 Schattauer Verlag or under

[0126] http:/www.customs.treas.gv/imp-exp/rulings/harmoniz/hrml29.html

[0127] on the Internet are particularly suitable for this purpose. Inparticular derivatives with penicillins, benzyl penicillin (PenicillinG), phenoxy penicillins, isoxazolyl penicillins, amino penicillins,ampicillin, amoxicillin, bacampicillin, carboxy penicillin, ticarcillin,temocillin, acyalamino pencillins, azlocillin, mezlocillin,piperacillin, apalcillin, mecillinam, cephalosporins, cefazolin group,cefuroxime group, cefoxitin group, cefoxitin, cefotetan, cefmetazole,latamoxef, flomoxef, cefotaxime group, cefozidime, ceftazidime group,ceftazidime, cefpirom, cefepim, other cephalosporins, cefsulodine,cefoperazone, oralcephalosporins of the cefalexine group, loracarbef,cefprozil, new oralcephalosporins with expanded spectrum, cefixime,cefpodoxim-proxetil, cefuroxime-axetil, cefetamet, cefotiam hexetil,cefdinir, ceftibutene, other β-lactam antibiotics, carbapenem,imipenem/cilastatin, meropenem, biapenem, aztreonam, β-lactamaseinhibitors, calvulanic acid/amoxicillin, clavulan

c acid/ticarcillin, sulbactam/ampicillin, tazobactam/piperecillin,tetracyclines, oxytetracycline, rolitetracycline, doxyc

line, minocycline, chloramphenicol, aminoglycosides, gentamic

, tobra

netilmicin, amikacin, spectinomyxin, macrolides

clarithromycin, roxithromycin, azithromycin, di

mycin, spiramycin, josamycin, lincosamides, clindamyc

, fusidic acid glycopeptide antibiotics, vancomycin, tecoplanin,pristina

in derivates, fosfomycin, antimicrobial folic acid antagonistsulphonamides, co-trimoxazole, trimethoprim, otherdiaminopyrimidine-sulphonamide combinations, nitrofurans,nitrofurantoin, nitrofurazone, Gyrase inhibitors (quinolones),norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin,fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles,antimycobacterial agents, isoniazid, rifampicin, rifabutin, ethambutol,pyrazinamide, streptomycin, capreomycin, prothionamide, terizidon,dapsone, clofazimine, topical antibiotics, bacitracin, tyrothricin,polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviralagents, acyclovir, ganciclovir, azidothymidine, didanosin, zalcitabin,thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine,foscarnet, amantadine, interferons, tibol derivatives, proteinaseinhibitors, antifungal agents, polyenes, amphotericin B, nystatin,natamycin, azoles, azoles for septic treatment, miconazole,ketoconazole, itraconazole, fluconazole, UK-109.496, azoles for topicalapplication, clotrimazole, econazole, isoconazole, oxiconazole,bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, tolnaftate,naftifine, terbinafine, amorolfine, anthraquinones, betulinic acid,semianthraquinones, xanthones, napthtoquinones, aryaminoalcohols,quinine, quinidines, mefloquine, halofantrine, chloroquine, amodiaquine,acridine, benzonaphthyridine, mepacrine, pyronaridine, dapsone,sulphonamide, sulfadoxine, sulfalenes, trimethoprim, proguanil,chlorproguanil, diaminopyrimidine, pyrimethamine, primaquine,aminoquinolines, WR 238,605, tetracycline, doxycyline, clindamycin,norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin,10b arte mether, arte ether, arte sunate, atovaquon, suramin,melarsoprol, nifurtimox, stibogluconate-sodium, pentamidine,amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide,praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin,bithionol, oxamniquine, metrifonate, piperazine, embonate can be [used].

[0128] The organophosphorus compounds can furthermore be present in thepharmaceutical preparations in combination with sulphonamide,sulfadoxin, artemisinine, atovaquon, quinine, chloroquine,hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesin,tetracyclines, doxycycline, proguanil, metronidazole, praziquantel,niclosamide, mebendazole, pyrantel, tiabendazole, diethylecarbamazine,piperazine, pyrivinum, metrifonate, oxamniquine, bithionol or suramin orseveral of these substances.

[0129] The above-listed pharmaceutical preparations are produced in theconventional manner by known methods, for example by mixing the activeingredient or active ingredients with the excipient or excipients.

[0130] The above-mentioned preparations can be used in humans andanimals either orally, rectally, parenterally, (intravenously,intramuscularly, subcutaneously), intracisternally, intra-vaginally,intraperitoneally, topically (powder, ointment, drops) and for thetreatment of infections in cavities, orifices. Suitable preparations areinjection solutions, solutions and suspensions for oral treatment, gels,infusions, emulsions, ointments or drops. Ophthalmological anddermatological formulations, silver and other salts, eardrops, eyeointments, powders or solutions can be used for topical treatment. Withanimals the absorption can occur via the food or drinking water insuitable formulations. Furthermore gels, powders, tablets, sustainrelease tablets, premixes, concentrates, granules, pellets, tablets,boli, capsules, aerosols, sprays, inhalers can be used with humans andanimals. The compounds used according to the invention can furthermorebe incorporated into other carrier materials such as, for example,plastics materials (plastics chains for topical treatment), collagen orbone cement.

[0131] In general it has proved advantageous both in human andveterinary medicine to administer the active ingredient or activeingredients of Formulae (I) and (II) in total quantities ofapproximately 0.05 to approximately 600, preferably 0.5 to 200 mg/kgbody weight every 24 hours, optionally in the form of several individualdoses in order to achieve the desired results. An individual dosecontains the active ingredient or active ingredients preferably inquantities from approximately 1 to approximately 200, in particular 1 to60 mg/kg body weight. It may however be necessary to deviate from theabove-mentioned dosages and this is dependent on the nature and the bodyweight of the patient to be treated, the nature and the severity of thedisease, the nature of the preparation and the application of thepharmaceutical composition as well as the time scale or interval withinwhich the administration takes place.

[0132] Thus in some cases it may be sufficient to get by with less thanthe above-mentioned quantity of active ingredient whilst in other casesthe above-stated quantity of active ingredient must be exceeded. Theperson skilled in the art can determine the optimum dosage and method ofapplication of the active ingredient required in each case by virtue oftheir expert knowledge.

[0133] The compounds according to the invention can be given in theconventional concentrations and preparations to animals together withthe feedstuff or the feedstuff preparations or with the drinking water.

EXAMPLE 1

[0134] Test of the Efficacy of Substances Against Malaria in vivo

[0135] The various derivatives were tested by the modified Peters' test.The substances were applied here in a quarter of the median lethal dose(LD50). In the test batch ten mice were infected with Plasmodiumvinckeii, the pathogen of mouse malaria. After confirmation of theinfection by blood testing four mice were treated. Six mice, which werenot treated, served as a control group. The treatment with 1,000mg/kg/d, 3-(N-formyl-N-hydroxylamino)-propylphosphonic acid monosodiumsalt over 3 days led to a destruction of the parasites in the mice'sblood. After just one day the treated group was free of livingparasites. The control mice had to be killed on day 5 after infectionwith parasitaemia of >80%. The treated mice were still free fromparasites 8 weeks after the treatment had stopped. Further experimentsshowed an efficacy of 50 mg/kg/d3-(N-formyl-N-hydroxylamino)-propylphosphonic acid monosodium salt inmice with a parasitaemia of 80%. These mice were also free of livingparasites after 1 day.

EXAMPLE 2

[0136] Protection from Malaria in a Test with Infected Mice

[0137] The efficacy of compounds in vivo against malaria was testedusing male mice weighing 20 to 25 g (BALB/c-strain). Four mice weretreated intraperitoneally with 50 mg/kg.3-(N-formyl-N-hydroxylamino)-propylphosphonic acid monosodium salt oneday before infection. The mice were then infected with Plasmodiumvinckeii. Mice which were not pretreated with the substance served as acontrol group. No infection could be detected in the treated mice,whilst the control mice were killed after 5 days with a parasitaemia of80%. The treated mice were still free of parasites 8 weeks afterinfection.

EXAMPLE 3

[0138] In vitro Cytotoxicity Against Malaria Parasites

[0139] On the Principle of IC50 Determination According to Vial et al(the Concentration at Which the Vitality of Parasites is Reduced by aHalf)

[0140] To determine the IC50 value according to Vial et al malariaparasites are initially cultivated for a complete 48 hour cycle in thepresence of inhibitors, in the subsequent 24 hours the survival rate ismeasured by [³H]-hypoxanthine insertion.

[0141] Carrying Out the Test

[0142] A dilution series of3-(N-formyl-N-hydroxylamino)-propylphosphonic acid monosodium salt isplaced in 20 μl aliquots concentrated by 10 on a microtitre plate. Then180 μl parasite suspension in culture medium is added to each well.Asynchronous cultures with a parasitaemia of approximately 0.4% and 2%haematocrite are used. The microtitre plates are subsequently incubatedfor 48 hours. Then 30 μl [³H]-hypoxanthine are added to each well. After24 hours of incubation the cells were harvested and the incorporatedradioactivity was measured. In FIG. 1 the results with the strains HB3and Dd2 are shown with known resistances against other malariapharmaceutical compositions. In both strains there is a IC50 value ofapproximately 100 μg/l. The resistances of these strains are:

[0143] Plasmodium falciparum HB3 (Honduras) is resistant topyrimethamine.

[0144] Plasmodium falciparum Dd2 (Indo-China) is resistant tocloroquine, quinine, pyrimethamine, cycloguanil and sulfadoxine.

[0145] No cross resistances with antimalarial agents were found.

EXAMPLE 4

[0146] Preparation of 3-Bromopropylphosphonic Acid Diethylester

[0147] 471 g (238 ml, 2.33 mol) 1,3-dibromopropane and 77.6 g (81 ml,0.467 mol) triethylphosphite were introduced into a 500 ml flask andheated for 30 minutes to 155-160° C. 20 ml ethyl bromide (boiling point:40° C.) were distilled off under normal pressure via a reflux condenserand a distilling apparatus. Concentration of the solution under vacuum(8 torr (1.07·10³ Pa)) resulted in 380 g (191 ml, 1.863 mol) 1.3dibromopropane (surplus educt). 88.1 g (0.34 mol) could be distilled asa colourless liquid (boiling point: 96° C., 0.1 torr (13.33 Pa)) fromthe remaining yellow oil. This corresponds to a yield of 73%. (Hewitt,Teese, Aust.J.Chem. 1984, 37, 205-10 U.S. Pat. No. 4,206,156).

[0148]¹H-NMR (CDCl₃) γ=4.08 (quintet, J=7 Hz, 4H), 1.33 (t, J=7 Hz, 6H)

[0149]¹³C-NMR (CDCL₃) γ=61.2 (OCH₂CH₃), 33.10 (J=18, 3 Hz), 25.6 (J=4, 4Hz), 24.14 (J=120, 6 Hz) 16.04 (OCH₂ CH₃)

EXAMPLE 5

[0150] Preparation of 3-(N-Hydroxyamino)-Propylphosphonic AcidDiethylester

[0151] Firstly 32.0 g (0.8 mol) of sodium hydroxide dissolved in 75 mlwater then 75 ml methanol, and finally 25.5 g (0.098 mol) 3-bromopropylphosphonic acid diethylester were added drop by drop to a solution of55.6 g (0.8 mol) hydroxylamine hydrochloride in 100 ml water withcooling with ice. This led to a clouding of the solution. After 3 hoursstirring at a temperature of 40 to 45° C. methanol was removed underreduced pressure, the resulting aqueous solution was saturated withNaHCO₃ (pH=8), shaken out three times with 60 ml toluene in each case(the toluene phase was discarded) and then shaken out with chloroform (1x with 90 ml, 2 x with 50 ml in each case). The slightly yellowychloroform phase was dried over MgSO₄. After filtering of thedehydrating agent the solution was concentrated under reduced pressure.15.43 g (0.0728 mol) 3-(N-hydroxyamino)-propylphosphonic aciddiethylester were obtained as an almost colourless oil. This correspondsto a yield of 74.3% (DE-A-27 33 658).

[0152]¹H-NMR (CDCl₃) γ=5.94 (wide s, 2H), 4.13 (quintet, J=7 Hz, 4H)2.90 (t, J=7 Hz, 2H) 1.5-2.2 (m, 4H), 1.33 (t, J=7 Hz, 6H)

[0153]¹³C-NMR (CDCL₃) γ=61.23 (OCH₂CH₃), 53.34 (NCH₂, J=15, 9 Hz), 22.75(J=141, 9 Hz), 19.77 Hz, 16.08 (OCH₂ CH₃)

EXAMPLE 6

[0154] Preparation of 3-(N-Hydroxyamino)-Propylphosphonic Acid

[0155] 12.9 g (0.0608 mol) 3-(N-hydroxylamino)-propylphosphonic aciddiethylester and 130 ml concentrated HCl were heated for 6 hours underreflux (oil bath temperature: 150° C.) . The resulting yellow/orangesolution is concentrated under reduced pressure. The remaining oil istaken up in 30 ml water, stirred with 3 spoonfuls of activated carbonfor 30 minutes, filtered out from the activated carbon and thecolourless solution is concentrated in the entire diaphragm pump vacuum.After take-up in 30 ml water a pH of 4.0 to 4.5 is adjusted withapproximately 4.7 g (0.056 mol) NaHCO₃ (from pH=1.5 the productprecipitates). Suction filtering of the white solid resulted in 5.83 g3-(hydroxyamino)-propylphosphonic acid (melting point: 160° C.,decomposition). This corresponds to a yield of 61.8%. (DE-A-27 33 658,Öhler Synthesis 1995, 539-543).

[0156]¹H-NMR (CDCl₃) γ=3.49 (t, J=7, 4 Hz, 2H), 2.1 (m, 2H), 1.82 (m,PCH₂, 2H)

[0157]¹³C-NMR (CDCL₃) γ=56.26 (NCH₂, J=15 Hz), 29.61 (PC, J=134 Hz),22.37 (C-2, J=3, 8 Hz).

EXAMPLE 7

[0158] Preparation of 3-(N-Formylhydroxyamino)-Propylphosphonic AcidDiethylester

[0159] 1.38 (0.030 mol) formic acid were added drop by drop at roomtemperature to 2.04 g (0.020 mol) acetic anhydride and stirred at thesame temperature. This solution was added with cooling with ice to 2.8 g(0.013 mol) 3-(N-hydroxyamino)-propylphosphonic acid diethylesterdissolved in chloroform. The reaction mixture is stirred for 30 minutesat 0-5° C. and for a further 1.5 hours at room temperature. Afterconcentration under reduced pressure until an oily residue is obtained,this oily residue is taken up in 15 ml methanol and 5 ml water, adjustedto pH=8 with 2 n NaOH and stirred for a further 1.5 hours at roomtemperature. Methanol is removed under reduced pressure and theresultant aqueous solution is adjusted to pH=5 with concentrated HCl.The yellow solution is extracted with chloroform (1×30 ml, 2×10 ml ineach case) and the CHCl₃ phases are dried over MgSO₄. Afterconcentration of the solution in the entire diaphragm pump vacuum 3 g ofa yellow oil are obtained. After removal of volatile constituents in theentire diaphragm pump vacuum, chromatography on 60 g SiO₂ withchloroform shows: methanol in the ratio 25:1 2.65 g product as yellowoil (DE-A-27 33 658).

[0160]¹H-NMR (CDCl₃) γ=8.4 (CHO, 0.5 H), 7.94 (CHO, 0.5 H), 4.1(quintet, 4 H), 3.68 (t, 2 H), 1.7-2.19 (m, 4 H) , 1.36 (t, J=7 Hz, 6 H)

[0161]³C-NMR (CDCL₃) γ=162.65 (CHO), 156.96 (CHO), 61.72 (OCH₂CH₃),46.31 (NCH₂, J=15, 9 Hz), 22.15 (PC, J=142, 0 Hz), 19.13 (C-2), 16.08(OCH₂ CH₃).

EXAMPLE 8

[0162] Preparation of 3-(N-Acetylhydroxyamino)-Propylphosphonic AcidDiethylester

[0163] 2.8 g (0.013 mol) 3,(N-hydroxyamino)-propylphosphonic aciddiethylester are dissolved in 30 ml methylene chloride and added drop bydrop with cooling with ice to 2.65 g (0.026 mol) acetic anhydride. Thereaction mixture is stirred for 30 minutes at 0-5° C. and for a further1.5 hours at room temperature. After concentration under reducedpressure until a yellow oily radical is achieved, this oily residue istaken up in 15 ml methanol and 5 ml water, adjusted to pH 8 with 2 nNaOH and stirred for a further 1.5 hours at room temperature. Methanolis removed under reduced pressure and the resultant solution is adjustedto pH=5 with concentrated HCl. The yellow solution is extractedrepeatedly with methylene chloride (1×30 ml, 2×10 ml in each case), thecombined CH₂Cl₂ phases are dried over MgSO₄ and the solvent is removedat room temperature under reduced pressure. 3.7 g of a yellow oil areobtained which are freed from adhering volatile substances in the entirediaphragm pump vacuum. 2.78 g yellow oil remain.

[0164]¹³C-NMR (CDCL₃) γ=171.96 (C=O), 61.62 (OCH₂CH₃), 47.44 (J=15, 49Hz), 22.13 (PC, J=141, 8 Hz), 19.3, 15.9 (OCH₂ CH₃).

EXAMPLE 9

[0165] Preparation of 3-(N-Formylhydroxyamino)-Propylphosphonic AcidMonosodium Salt

[0166] 2 ml formic acid are added drop by drop to 4 ml acetamide at 0-5°C. The solution is stirred at this temperature for 10 minutes and for afurther 15 minutes at room temperature, subsequently cooled to 0° C.again and 3.28 g (0.021 mol) 3-(N-hydroxyamino)-propylphosphonic aciddissolved in 6 ml formic acid are added drop by drop at 0-5° C. After 1hour of stirring at room temperature the solution is condensed in arotary evaporator under reduced pressure, the oil is dissolved in 50 mlmethanol, heated to 60° C. and mixed with 10 ml ethanol. The resultingoily separated material is separated without stirring by decanting. Toprecipitate white crystals the methanolic solution is mixed with afurther 50 ml ethanol, boiled up and the white residue filtered out.This residue is taken up in 80 ml methanol and 100 ml ethanol are addedwith stirring. The mixture is stirred further.overnight at roomtemperature. A solid is obtained which is filtered out. (DE-A-27 33 658)

EXAMPLE 10

[0167] Preparation of 3-(N-Acetylhydroxyamino)-Propylphosphonic AcidMonosodium Salt

[0168] A suspension of 3.8 g (0.02 mol)3-(N-hydroxyamino)-propylphosphonic acid is introduced into 20 ml waterand 4.51 g (0.044 mol) acetic anhydride are added drop by drop at roomtemperature. After the solution has been stirred for 1.5 hours at roomtemperature a pH of 2.5 is adjusted with 0.2 n NaOH, the solution isconcentrated in the entire diaphragm pump vacuum, taken up twice in 40ml water in each case, which are again removed by concentration and theoil is washed twice with 30 ml ether in each case, taken up in 50 mlwater and a pH of 6.5 is adjusted with 1.6 g NaHCO₃. After removal ofvolatile constituents under vacuum, 20 ml n-butanol are added to removethe residual water and are also removed under reduced pressure. The oilis boiled up twice with isopropanol, the isopropanol phase is discardedand the remaining glassy resin is pulverlsed with a spatula to a yellowsolid (5.65 g). In order to recrystallise it, it is taken up in only alittle methanol, filtered from the undissolved component and acetone isadded dropwise to the filtrate. A first filtering results in 1 g productwith a melting point of 175° C. Recrystallisation as described above iscarried out again for further purification. (DE-A-27 33 658)

EXAMPLE 11

[0169] Preparation of Antiparasitically Effective Agents

[0170] Preparation for injections:

[0171] (1) The required quantity of sterile antiparasitically effectiveagent, 3-(N-formyl-N-hydroxylamino)-propylphosphonic acid monosodiumsalt was divided into phials or ampoules which then contained 500 mgactive ingredient. The phials were hermetically sealed to excludebacteria. For injections 2 ml sterile water were added to the phials ineach case and the content was administered.

[0172] In substantially the same manner as described under (1) furtherinjectable preparations of the antiparasitically effective agent wereprepared as described below:

[0173] (2) 250 mg 3-(N-formyl-N-hydroxylamino)-propylphosphonic acidmonosodium salt were used as active ingredient for the injections.

[0174] (3) 250 mg3-(N-formyl-N-hydroxylamino)-trans-1-propenyl-phosphonic acid monosodiumsalt were used as active ingredient for the injections.

[0175] (4) 500 mg3-(N-acetyl-N-hydroxylamino)-2-hydroxypropyl-phosphonic acid monosodiumsalt were used as active ingredient for the injections.

[0176] (5) 250 mg3-(N-formyl-N-hydroxylamino)-2-hydroxypropyl-phosphonic acidmonopotassium salt were used as active ingredient for the injections.

[0177] Preparation of tablets:

[0178] A suitable tablet recipe is formed by the following mixture:3-(N-formyl-N-hydroxylamino)-propylphosphonic 200 mg acid monosodiumsalt Mannitol 400 mg Starch  50 mg Magnesium stearate  10 mg

[0179] Preparation of capsules:3-(N-formyl-N-hydroxylamino)-propylphosphonic 300 mg acid monopotassiumsalt Magnesium stearate  15 mg

[0180] The present components were mixed and then introduced into a hardgelatine capsule in the conventional manner.

[0181] Preparation of an oily suspension:3-(N-acetyl-N-hydroxylamino)-propylphosphonic 200 mg acid monosodiumsalt Lanette-Wax SX ®  50 mg Soft paraffin 100 mg Brilliant blue FCF  25mg

[0182] The above components were mixed with liquid paraffin for a totalquantity of 3 g to achieve an infusion preparation.

[0183] Examples of Methods of Synthesis for Substances with theFollowing Structure:

 where R₁=R₂=C₁₈H₃₇  12

where R₁=H or Na⁺and R₂=C₁₈H₃₇   13

where R₁=H or Na⁺and R₂=C₁₆H₃₃   14

EXAMPLE 12

[0184] 3-(N-Formyl-N-Hydroxylamino)-Propylphosphonic AcidDioctadecyl-Ester 12

[0185] 1 equivalent fosmidomycin (FR-31564) and 6 equivalentstris(octadecyl)-orthoformic acid were heated under reduced pressure andvigorous stirring for 2 hours under reflux. Then methanol and formicacid octadecylester were distilled off—also under reducedpressure—wherein the temperature must be kept below the decompositiontemperature of the product. Further volatile secondary products areremoved in the oil pump vacuum in order finally to obtain 12 as a highlyviscous oil. (On the carrying out of the procedure cf.: D. A. Nicholson,W. A. Cilley, O. T. Quimby, J Org Chem. 1970, 35, 3149-50)

[0186] The monoesters can be provided starting from both fosmidomycinand di-octadecylester 12.

EXAMPLE 13

[0187] 3-(N-Formyl-N-Hydroxylamino)-Propylphosphonic AcidMonooctadecyl-Ester 13

[0188] First proposal:

[0189] 0.21 mmol fosmidomycin (phopsphonic acid) and 0.2 mmoln-octadecanol are dissolved in 1-2 ml dry pyridine and 0.67 mmoltrichloracetonitrile is added dropwise thereto. The reaction mixture isheated for 16 hours to 80° C. and then condensed under vacuum. Aftertake up in water (for the diaphragm filtering of undissolved components)the solution is condensed again under reduced pressure and the productis chromatographed onto silica gel with ethyl acetate, ethanol and wateras eluent. The product 13 is produced in this case as a viscousrubber-like to glass-like compound.

[0190] (On the carrying out of the procedure cf.: G. B. Brookes, D.Edwards, J. D. I. Hatto, T. C. Smale, R. Southgate, Tetrahedron 1995,51, 7999-814)

[0191] Second proposal:

[0192] 0.2 mmol of the diester3-(N-formyl-N-hydroxylamino)-propylphosphonic acid dioctadecylester 13dissolved in ethanol is added to 1 equivalent KOH (ethanolic solution)and boiled for 10 hours under reflux. Owing to the introduction of CO₂,potassium salts can precipitate as carbonates and can be removed byfiltration. The filtrate is condensed to dryness, the oil is dried overP₂O₅ washed with petrol ether and the product can finally berecrystallised from absolute ethanol by the addition of isopropanol.

[0193] (On the carrying out of the procedure cf.: V. Jagodic, Chem Ber1960, 93, 2308-13)

EXAMPLE 14

[0194] 3-(N-Formyl-N-Hydroxylamino)-Propylphosphonic AcidMonohexadecyl-Ester 14

[0195] 14 can be synthesised in the same way as 13.

1. Use of organophosphorus compounds of the general formula (I)

in which r₁ and r₂ are the same or different and are selected from thegroup which consists of hydrogen, substituted and unsubstituted alkyl,substituted and unsubstituted hydroxyalkyl, substituted andunsubstituted alkenyl, substituted and unsubstituted alkinyl,substituted and unsubstituted aryl, substituted and unsubstituted acyl,substituted and unsubstituted cycloalkyl, substituted and unsubstitutedaralkyl, substituted and unsubstituted heterocyclic radical, halogen,OX₁ and OX₂, wherein X₁ and X₂ may be the same or different and areselected from the group which consists of hydrogen, substituted andunsubstituted alkyl, substituted and unsubstituted: hydroxyalkyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkinyl, substituted and unsubstituted aryl, substituted andunsubstituted acyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted aralkyl, substituted and unsubstitutedheterocyclic radical, A is selected from the group which consists of analkylene radical, an alkenylene radical and a hydroxyalkylene radical,R₃ and R₄ are selected independently from the group which consists ofhydrogen, substituted and unsubstituted alkyl, substituted andunsubstituted hydroxyalkyl, substituted and unsubstituted aryl,substituted and unsubstituted acyl, substituted and unsubstitutedaralkyl, substituted and unsubstituted alkenyl, substituted andunsubstituted alkinyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocyclic radical, halogen, OX₃ andOX₄, R₃ and R₄ are selected independently from the group which consistsof hydrogen, substituted and unsubstituted C₁₋₂₆-alkyl, substituted andunsubstituted hydroxy-C₁₋₂₆-alkyl, substituted and unsubstituted aryl,substituted and unsubstituted acyl, substituted and unsubstitutedaralkyl, substituted and unsubstituted C₁₋₂₆-alkenyl, substituted andunsubstituted C₁₋₂₆-alkinyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocyclic radical, halogen, OX₃ andOX₄, wherein X₃ and X₄ are selected independently from the group whichconsists of hydrogen, substituted and unsubstituted C₁₋₂₆-alkyl,substituted and unsubstituted hydroxyl-C₁₋₂₆-alkyl, substituted andunsubstituted aryl, substituted and unsubstituted aralkyl, substitutedand unsubstituted C126- alkenyl, substituted and unsubstitutedC₁₂₆-alkinyl, substituted and unsubstituted cycloalkyl, substituted andunsubstituted heterocyclic radical, a silyl, a cation of an organic andinorganic base, in particular a metal of the first, second or third maingroup of the periodic system, ammonium, substituted ammonium andammonium compounds which derive from ethylene diamine or amino acids,and their pharmaceutically acceptable salts, esters and salts of estersor else compounds which upon application provide the compounds to beused according to the invention as metabolic products or decompositionproducts in order to produce a pharmaceutical composition fortherapeutic and prophylactic treatment of infections in humans andanimals caused by parasites, fungi and viruses.
 2. Use according toclaim 1, characterised in that the organophosphorus compounds correspondto Formula (II),

wherein, X₁ is selected from the group which consists of hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclic radical.
 3. Use according to claim 2, characterised in thatR₂ is an acyl radical, preferably an alkanoyl radical and particularlypreferably a formyl or acetyl radical.
 4. Use according to one of thepreceding claims, R₃ and R₄ are selected independently from the groupwhich consists of hydrogen, methyl, ethyl, OX₃ and OX₄, wherein X₃ andX₄ are selected independently from the group which consists of hydrogen,sodium, potassium, methyl and ethyl.
 5. Use according to one of thepreceding claims, characterised in that between the phosphorus atom andthe nitrogen atom A forms a chain of three carbon atoms, preferably apropylene, propenylene or hydroxypropylene chain.
 6. Use according toclaim 1 or 2, characterised in that R₄ represents OX₄ and X₄ is selectedfrom the group which consists of hydrogen, ammonium and metals of thefirst and second main group of the periodic system, preferably sodium,potassium, calcium or magnesium, ammonium compounds which derive fromethylenediamine or amino acids, preferably ethanolamine,ethylenediamine, N,N-dibenzylethylenediamine and arginine.
 7. Useaccording to one of the preceding claims for the treatment of infectionswhich are caused by viruses selected from the group which consists ofviruses of the genus parvoviridae, in particular parvo viruses, dependoviruses, denso viruses, viruses of the adenoviridae genus, in particularadeno viruses, mastadeno viruses, aviadeno viruses, viruses of the genuspapovaviridae, in particular papova viruses, in particular papillomaviruses (so called wart viruses), polyoma viruses, in particularJC-virus, BK-virus and miopapova viruses, viruses of the genusherpesviridae, in particular herpes simplex viruses, of thevaricella-zoster viruses, human cytomegalo virus, Epstein-Barr viruses,human herpes virus 6, human herpes virus 7, human herpes virus 8,viruses of the genus poxviridae, in particular pox viruses, orthopox,parapox, molluscum contagiosum virus, avipox viruses, capripox viruses,leporipox viruses, primary hepatotropic viruses, in particular hepatitisviruses, such as hepatitis A viruses, hepatitis B viruses, hepatitis Cviruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses,hepatitis G viruses, hepadna viruses, in particular all hepatitisviruses, such as hepatitis B virus, hepatitis D viruses, viruses of thegenus picornaviridae, in particular picorna viruses, all entero viruses,all polio viruses, all coxsackie viruses, all echo viruses, all rhinoviruses, hepatitis A virus, aphtho viruses, viruses of the genuscalciviridae, in particular hepatitis E viruses, viruses of the genusreoviridae, in particular reo viruses, orbi viruses, rota viruses,viruses of the genus togaviridae, in particular toga viruses, alphaviruses, rubi viruses,.pestiviruses, rubella virus, viruses of the genusflaviviridae, in particular flavi viruses, ESME virus, hepatitis Cvirus, viruses of the genus orthomyxoviridae, in particular influenzaviruses, viruses of the genus paramyxoviridae, in particular paramyxoviruses, morbilli virus, pneumo virus, measles virus, mumps virus,viruses of the genus rhabdoviridae, in particular rhabdo viruses, rabiesvirus, lyssa virus, viscula stomatitis virus, viruses of the genuscoronaviridae, in particular corona viruses, viruses of the genusbunyaviridae, in particular bunya viruses, nairo virus, phlebo virus,uuku virus, hanta virus, hantaan virus, viruses of the genusarenaviridae, in particular arena viruses, lymphocytic choriomeningitisvirus, viruses of the genus retroviridae, in particular retro viruses,all HTL viruses, human T-cell leukaemia virus, oncorna viruses, spumaviruses, lenti viruses, all HI viruses, viruses of the genus filoviridaein particular Marburg and Ebola virus, slow viruses, prions, oncovirusesand leukaemia viruses.
 8. Use according to one of the preceding claimsfor the prevention and treatment of infections caused by unicellularparasites namely pathogens of malaria, sleeping sickness, Chagas'disease, toxoplasmosis, amoebic dysentery, leishmaniasis,trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiasis,sarcocystosis, acanthamebiasis, naegleriasis, coccidiosis, giardiasisand lambliosis.
 9. Use according to one of claims 1 to 8 in apharmaceutical preparation which has an active content of at least oneorganophosphorus compound and a pharmaceutically acceptable carrier. 10.Use according to claim 9, characterised in that the pharmaceuticalpreparation has at least one further pharmaceutical active ingredient,in particular sulphonamide, sulfadoxine, artemisinin, atovaquon,quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine,pyrimethamine, armesin, tetracyclines, doxycycline, proguanil,metronidazole, praziquantel, niclosamide, mebendazol, pyrantel,tiabendazol, diethylcarbazine, piperazine, pyrivinum, metrifonate,oxamni-quine, bithionol or suramin.
 11. Use according to claim 10,characterised by one or more components of the group which consists ofbenzyl penicillin (Penicillin G), phenoxy penicillins, isoxazolylpenicillins, amino penicillins, ampicillin, amoxicillin, bacampicillin,carboxy penicillin, ticarcillin, temocillin, acyalamino pencillins,azlocillin, mezlocillin, piperacillin, apalcillin, mecillinam,cephalosporins, cefazolin group, cefuroxime group, cefoxitin group,cefoxitin, cefotetan, cefmetazole, latamoxef, flomoxef, cefotaximegroup, cefozidime, ceftazidime groups, ceftazidime, cefpirom, cefepim,other cephalosporins, cefsulodine, cefoperazone, oralcephalosporins ofthe cefalexine group, laracarbef, cefprozil, new oralcephalosporins withexpanded spectrum, cefixime, cefpodoxim proxetil, cefuroxime axetil,cefetamet, cefotiam hexetil, cefdinir, ceftibutene, other β-lactamantibiotics, carbapenem, imipenem/cilastatin, meropenem, biapenem,aztreonam, β-lactamase inhibitors, calvulanic acid/ amoxicillin,calvulanic acid/ticarcillin, sulbactam/ampicillin,tazobactam/piperacillin, tetracyclines, oxytetracycline,roli-tetracycline, doxycycline, minocycline, chloramphenicol,amino-glycosides, gentamicin, tobramycin, netilmicin, amikacin,spectinomyxin, macrolides, erythromycin, clarithromycin, roxithromycin,azithromycin, dirithromycin, spiramycin, josamycin, lincosamides,clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin,tecoplanin, pristinamycin derivates, fosfomycin, antimicrobial folicacid antagonists, sulphonamides, co-trimoxazole, trimethoprim, otherdiaminopyrimidine-sulphonamide combinations, nitrofurans,nitrofurantoin, nitrofurazone, Gyrase inhibitors (quinolones),norflaxacin, ciproflaxacin, ofloxacin, sparfloxacin, enoxacin,fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles,antimycobacterial agents, isoniazid, rifampicin, rifabutin, ethambutol,pyrazinamide,. streptomycin, capreomycin, prothionamide, terizidon,dapsone, clofazimine, topical antibiotics, bacitracin, tyrothricin,polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviralagents, acyclovir, ganciclovir, azidothymidine, didanosin, zalcitabin,thiacytidine, stavudine, ribavirin, idoxuridine, trifluridine,foscarnet, amantadine, interferons, tibol derivatives, proteinaseinhibitors, antifungal agents, polyenes, amphotericin B, nystatin,natamycin, azoles, azoles for septic treatment, miconazole,ketoconazole, itraconazole, fluconazole, UK-109.496, azoles for topicalapplication, clotrimazole, econazole, isoconazole, oxiconazole,bifonazole, flucytosine, griseofulvin, ciclopiroxolamine, tolnaftate,naftifine, terbinafine, amorolfine, anthraquinones, betulinic acid,semianthraquinones, xanthones, napthtoquinones, aryaminoalcohols,quinine, quini-dines, mefloquine, halofantrine, chloroquine,amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine,dapsone, sulphonamide, sulfadoxine, sulfalenes, trimethoprim, proguanil,chlorproguanil, diaminopyrimidine, pyrimethamine, primaquine,aminoquinolines, WR 238,605, tetracycline, doxycyline, clinda-mycin,norfloxacin, ciprofloxacin, ofloxacin, artemisinin, dihydroartemisinin,lOb arte mether, arte ether, arte sunate, atovaquon, suramin,melarsoprol, nifurtimox, stibogluconate-sodium, pentamidine,amphotericin B, metronidazole, clioquinol, mebendazole, niclosamide,praziquantel, pyrantel, tiabendazole, diethylcarbamazine, ivermectin,bithionol, oxamniquine, metri-fonate, piperazine, embonate.